Method for producing 1-hydroxyisoquinolines



Patented Jan. 16, 1951 UNITED STATES PATENT OFFICE METHOD FOR PRODUCING l-HYDROXY- ISOQUINOLINES Glenn E. Ullyot, Philadelphia, Pa., assignor to Smith, Kline 8: French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing.

Claims.

This invention relates to a method for the preparation of pyridine derivatives of certain sti 'cture which find utility as intermediates in 'tllf preparation of further compounds which have physiological activity as anesthetics and as antispasmodic agents.

The process in accordance with this invention is adapted for the production of pyridine derivatives having the following structure:

:where R is a member of the group consisting of hydrogen, alkyl groups having not more than ten carbon atoms, a phenyl group and phenylalkyl groups, the alkyl portionof which has not more than three carbon atoms; R andR are members of the group consisting of hydrogen, hy-

' droxyl, methyl, methoxy, ethoxy, amino, acylwhere R, R" and R' are as given above;

For the preparation of typical starting materialshaving the above structure for the preparation of compounds according to this invention see Ullyot, et al. Journal Organic Chemistry,

vol. 10, pp. 429-440 (1945), United States Letters Patent No. 2,473,484, dated June 14, 1949, and Ullyot, Taylor and Dawson Journal American Chemical Society, '70, 542 (1948),

More specifically, in'proceeding according to the method embodying this invention, to a solu--' tion of a salt of an amine having the above lormula in any suitable solvent, such as Water,

aqueous ethanol, aqueous isopropanol, or the like,

is added an alkali such as sodium hydroxide, po-

tassium hydroxide. ammonia, or the like, and

Application September 20,1949, Serial N0. 116,867

V 2 I the resulting solution is allowed to stand at room temperature until rearrangement occurs. If desired,and for a saving of time it generally will be desirablathe solution or mixture of the amine salt and alkali may be heated to hasten the rearrangement.

If desired one may start with an amine base of the above structure, in which case use of an alkali, While desirable, will not in all cases be necessary.

' When the rearrangement has occurred, the rearranged product will, in certain cases, separate from the solution and may be readily recovered. Again, where the rearranged product does not readily separate from the solution, separation may be accomplished by concentrating the solution and cooling.

The rearrangement will result in production of a compound having the following structure:

Intermediate I Final product where R, R" and R' are as given above; and

which is useful as an intermediate for the preparation of various substituted compound having physiological action.

More specifica ly, the dehydration may be effected by dissolving the compound Intermediate I in convenient amounts of H2504, for example, 5 parts by weight to one of the compound to be dehydrated and warming the resultant solution on steam bath for to 3 hours to effect removal of accordance with this invention:

water. With some compounds heating will be unnecessary. The solution is then poured into cold water and the resultant precipitate collected and recrystallized from a suitable solvent, such as ethyl alcohol, isopropyl alcohol.

Dehydration :mayalso be effected by dissolving the compound in benzene or siniilarsolven't and treating with a suitable dehydrating agent, such as KHsOi, P205, or the like, at a temperature ofto80C. I 7

Alternatively, in some cases, the conversion {of Intermediate I to the final product maybeaccomplished by heating Intermediate I to a temperature of 10 C.-100 Cpab'ov'e its melting point, depending upon the particular intermediate.

As more specifically illustrative of ,procedure in accordance with this inventionfanamine salt having the structure given above will be dissdlve'd in a convenient amount of water, for example,

0.1 m. of amine salt'E in 100 cc. of water, and

:either one or two equivalent amounts-of alkali,

as sodium or potassium hydroxide, added to the solution. The alkali solution will desirably be heated to facilitate the rearrangement with promlduction of a compound having the str-ucture of Intermediate I above, which when dehydrated by treatment with thedehydrating agent at a temperature within'the range room temperatureto '80? C. for about ,fourhours, depending upon the temperature used, results in a compoundrhaving the:str ucture noted above asthe final product.

By way of specific illustration-of procedure in "EXAMPLE'I LZ-dihydrozsoquindlon-1 H For the preparation """of 4-hydroxy-1,2,3,4- tetrahydroisoquinolon-l, 79.8 grams of aminophthalidylmethane hydrochloride was dissolved in 109 cc. of warmiwa'ter; 'f'Twenty-eight cubic centimeters of 40% s'odiumhydroxide were-added and the solution was heated 'on a-stea'm bath forfive hours.

overnight, 68.3 --g. "of 'a crystalline product were After the reaction mixture stood isolated. I

"1,2 dihydroisoquinolon-l will 'thenbe-prepared "by adding one part of 4-hydroxy- 1,2j3;4 tetrahydroisoquinolon-l to three" to 'six parts of concentrated sulfuric acid while "stirrin'g'and cooling, to keep the temperature from risingab'oveab'out 70 C. The resulting solution isithen heated on a steam bath for 1-3 hours, cooled and poured into ice water. The resulting precipitate is collected and recrystallized from methanol or isopropanol.

' EXAMPLE 2 This compound will be prepared using the procedure described in Example- 1, except that 1-amfno-l-phthalidylethane will be used "as a ;:,starting material vto be rearrangedinwalkaline medium and subsequently dehydrated.

2,538,341 if?? xiii 3:03.72

EXAMPLE 3 3-ethyZ-L2-dihydroisoquinoZon-1 This compound will be prepared using the procedure described in Example 1, except that 1=amin0 1-phthalidylbutane'will be used as a starting materi'l to be rearranged in" alkali e medium and-subsequently dehydrated EXAMPLE 5 3-butyl-1,Z-dihydroisoquinolon-I This compound will be prepared using the procedure describedlin' Example '1, excepti'that fl-amino lephthalidylpentane' will be used as' a starting material to be rearranged/in 'akaline medium and subsequently dehydrated.

EXAMPLES "3ein z ay-aimeth iz-i;2- im}arqiw umozonq This compound'will beprepared by heating an alkaline solutionof 1 -amino l (5,6 dimethyl phthalidyl) -propa'ne' as starting material followed by subsequent dehydration following the proceduredescribed in Example 1 above E M i ,v -3-methyl-6,7- dichZoro-1,2dihydroisoquinolonl This compound will "be :prepared by heating an alkaline solution of 1 amino- 1 '(5,6--dichloro p'hthalidyl) ethane .pas 'zstarting material followed :by subsequent dehydration following "the apro- :cedure described iii-Example lu abbv e. .11

.r-aoaaan This compound will be prepared by heating an 1 alkaline solution of amino 6 ethylphthalidyl 1: methane as starting material followed by subsequent dehydration following the procedure described in Example l above.

I I v EXAMPLE 9 V 7 3-p1'0p3/Z-6J-dim'ethoxy-1,Z-dihydroisloQuinolon-Z CHaO- CHaO This compound will be prepared by heating 'alkaline solution of l-amino-l-(5,6-dimethoxy- 'phthalidyl) -butane as starting material followed by subsequent dehydration following the procedure described in Example 1 above.

EXAMPLE 1o 3-butyl-7,8dimethoa:y-1,Z-dihydroidduinolon-I onto I EH This compound will be prepared by heating an alkaline solution of l-amino-l-(6,7-dimethoxy- 'phthalidyl) -'pentane as starting materialffol- EXAMPLE 13 3 phenylisopropylJ-bromo4,2

' dihydroisoquinolon-I BF N c113 c-cHr-cH- g v a v i This compound will be prepared by heating an alkaline solution of 1 amino 1' (6 bron'iophthalidyl) -3-phenylbutane as starting material followed by subsequent dehydration following the procedure described in Example 1 above.

EXAMPLE 14 .7

3-ethyl-7-amino-1,Z-dihydroisoguinolon-I This compoundwas prepared by the rearrangement of 1 amino 1 (6 aminophthalidyl) propane dihydrochloride, which in turn was prepared 'by the reduction of 1 (6 nitrophthalidyl) 1- nitropropane as described below. This starting material, the dinitrophthalidyl-propane in turn was prepared in the following manner, using lowed by .subsequent dehydration following-the I. 'CH

This compound will be prepared by heating an alkaline solution of l-amino-l-(6,7edimethoxy- TphthalidyD-pentane as starting material followed by subsequent dehydration following the procedure described in Example 1 above.

I EXAMPLE 12 6,7-dihydr0xy-3-benayl-1,Z-dihydroisoquinolon-I s. OH

Ho N

&HCH2- Ce This compound will be prepared by heating an alkaline solution of l-amino-l-(5,6-dihydroxyphthalidyl) -2-phenylethane as starting material -followed' by subsequent. dehydration following the .proceduredescribed in Example 1 above.

generally the procedure ofShriner and Keyser (J. Org. Chem volume 5, 200 (1940)).

A solution of 22.1 gms. of l-nitro-l-phthalidylpropane melting at 94-96" C. in 20 ml. of concentrated sulfuric acid was added dropwise with stirring to a mixture of 11 gms. of potassium .nitrate and 33 ml. of concentrated'sulfuric acid, the reaction temperature being maintained lower than 5? C. After stirring for threehours at less than 10 C., the mixture was allowed to stand at room temperature for 16 hours and poured over cracked ice. The granular solid which separated was filtered and dried and melted' at 93-96 C. Recrystallization from alcohol provided a product melting at 95-98 C.

30 gms. of the above dinitrophthalidylpropane was reduced using 160 cc. of glacial acetic'acid and 0.1 gm. of platinum oxide at a temperature of -80. 100% of the theoretical volume of hydrogen corresponding to the reduction of one nitro group was taken up in a period of 10 minutes, after which further absorption of hydrogen was very slow. The hot solution was removed, filtered and cooled whereupon a light orange product was separated by filtration, which melted at 178-l8l C. Further purification by refluxing in alcohol and butanone followed by distillation yielded "a 0 purer product of l-(fi-aminophthalidyl) -l-nitro- 0 made definitely alkaline by the addition of excess 40% sodium hydroxide solution to effect rearrangement to the corresponding isoquinolon. The resulting mixture was heated at 90 C. under vacuum and 1.5 liters of water was slowly distilled for a period of six hours. Heating was then confor;1.5 hoursv poured into1250 gmsrofcraokedice; Theresulting solution being made: alkaline. with. 40%; sodium and further filtered to remove additional salt,.

and cooled over a long period of time. The yield was a white crystalline powder product of '7- amino-3 ethyl-4-hydroxya1,2,3,4 tetrahydroisoquinolon-l which meIted'at-ZIGP'ZI'ZP C.

A solution of 21 g. of crude"'7-amino-3-ethyl-4- .10

hydroxy-1,2g3;sl-tetrahydroisoquinolonrl. in. 64 cc. of'concentrated sulfuric. acid waslheate'd .at 80-90 It. was then cooled; to 30' and hydroxide, a tan solid formed which was removed by filtration, washed with water, and dried at 45; which product. melted at; 5195491? (1. Three recrystallizations from the alcohol raised the melting point to 202203 C.

EXAMPLE 1'5 7 acetyZamzno-3-ethyZ-4,2-dihydr0is0quin0lon-1 omoo-NH- v dihydroi'soquinolon-l (prepared as 'anintermediate in Example 4 above) in 5 cc: ofwarm glacial aceticacid'was dilutedwith'fiifi cct'ofwater. The

resulting solution was cooled to 35 and 0.8

(L008 n1) of aceticanhydride was added. The

' resulting solution was shaken intermittently for 21' hours at room temperature, diluted with 5 cc; of water and cooledto 5. Separation" of the 'pro'duct'is' accomplished by filtration, followed by "washing with water and drying. The resulting material was completely soluble in G-N-hydrochloricacid and melted at 274-277 (I. Crystallization from acetic'acid and'water gavean almost.

white product which melted at 276 278" C.

EXAMPLE? 1a:

.I-ethyFT-butyryZamino- 1,2 dihydroz'soqu'z'no Ion-1 This compound will be prepared by rearrangement of l-amino-l- (6-butyrylaminophthalidyl)- propane dlhydrochloride. using, the. procedure of Example 14 ffollowedby. dehydration. to the. cor-- N-butyryl'ation. Thenitro groupof themesulting.

hutyry'lamino compound is then. reduced using theproceduraoi Example. 14.. V

OH CH3:

"hexane hydrochloride i'n 25 cc; of'warm water is 'amin'ophenylphthalidylmethane' This compound isprepared by the rearrangement of 1. (6. dimethylaminophthalidyl) 1- aminopropane using the procedure of Example 14 followed by dehydration to the corresponding dihydroisoquinolon; The starting material is prepared from 4 I-(G-aminophthalidyl) -1-nitropropane prepared as an intermediate in Example 14. This compound is methylated on the amino group by treatmentiwithformaldehyde and formic "acid according to the procedure of Clark et al., J. A. 'C; S. 55'; 4571 (1933)".

The nitrogro'up or the'resulting' dimethyl'amino compound is-re'duced to the corresponding amino" compound usingthe procedure "of Example 14'.

EXAMPLE 18 3-phenyl-1,Z-dihydroisoquinolon-I OH v This compound is prepared by rearranging (phenylphthalidyl carbinamine') followed by dehydration to the corresponding dihydroisoquirrolon by the procedure of Example 1.

EXA PLE 19 3-n-amyl-1,Z-dihydroisoquinoloml C|---C5H11 To,a solution of 1.0 g. of l-amino-l-phthalidyladdedga solution of"0.4" g. of' sodium hydroxid'elin 5. cc. of water. I The resulting mixture 'is' heated just below reflux for 20 hours: The oil which separates is taken into ch'o'lorororm and the chloroform is removed by distillation in vacuo. The white solid which remains'is dissolvedin 7.5 cc. of concentrated sulfuric acid and this solution is heated at 75 for 35 minutes. It is then cooled and poured into, cracked ice. The white solid is removed by filtration; washed with water and recrystallized three times from isopropanol, melting at 106.5-108.

The compounds produced by the method in accordance with this invention will be used as 'i'nterm ='.-diates for the production of corresponding aminoalkoxyisoquinoline derivatives having physiological properties by treating them' with a reagent; as, for example, phosphorous oxychloride, to produce the corresponding l-chloroisoquinoline derivatives and reacting such derivatives with an amino alcohol of the formula YROH where Y isa tertiary nitrogen linked amino group including a member of the group consisting of aliphatic groups of. not over ten carbon atoms, a pyridine group an'd'where N is a member of thegroup containing not more than six carbon atoms.

More specifically, the intermediates produced by the dehydration of compounds in accordance with: this invention will be converted to: the 1-ch10roderivatives by heating: under reflux um .tilthe evolution of oxygen: chloride-ceases; The

excessoxychlorideis;thenzremoved by'di'stillatlon and thezproducthpurified by distillation: imvacuo'.

The l-chloro derivatives are then treated with an alkali metal derivative of an amino alcohol of the type indicated by adding the l-chloro derivative to a suspension or solution of the alkali metal derivative of the amino alcohol, the addition being made rapidly with stirring, followed by heating, with continued stirring, to a temperature up to the boiling point of the solvent. On completion of the reaction, the reaction mixture is cooled and evaporated to remove precipitated metal chloride, the solvent removed by distillation and the aminoalkoxyisoquinoline derivative purified by distillation in vacuo, all as more specifically disclosed in application for United States Patent filed by me August 20, 1948, Serial No. 45,432, now abandoned.

This application is a continuation-in-part of application filed by me August 1'7, 1946, Serial No. 691,394, now abandoned.

What is claimed is: l

1. The method of producing an isoquinoline derivative having the structure where R is a member of the group consisting of hydrogen, alkyl groups having not more than ten carbon atoms, a phenyl group and phenylalkyl groups, the alkyl portion of which has not more than three carbon atoms; R and R are members of the group consisting of hydrogen, hydroxyl, methyl, methoxy, ethoxy, amino, acylamino having not in excess of five carbon atoms and alkylamino having not in excess of three carbon atoms, the said substituents being so chosen that the number of nitrogen atoms in the substituents does not exceed one, which com- 10 prises rearranging a compound having the structure in which R, R" and R' are as given above, by dissolving said compound in a solvent therefor and dehydrating the product of the rearrangement.

' 2. The method of producing an isoquinoline derivative according to claim 1, characterized by the fact that an alkali is included in the solution formed.

3. The method of producing an isoquinoline derivative according to claim 1, characterized by the fact that the solution formed is heated to a temperature below the boiling point of the solvent.

4. The method of producing an isoquinoline derivative according to claim 1, characterized by the fact that the solvent is selected from the group consisting of water and a monohydric alcohol.

5. The method of producing an isoquinoline derivative according to claim 1, characterized by the fact that the solvent is selected from the group consisting of water and a monohydric alcohol and that the solution formed is heated to a temperature below the boiling point of the solvent.

GLENN E. ULLYOT.

REFERENCES CITED The following references are of record in the file of this patent:

Ullyot et al.: J. Org. Chem., vol. 10, pages 429-440 (1945). 

1. THE METHOD OF PRODUCING AN ISOQUINOLINE DERIVATIVE HAVING THE STRUCTURE 